Acetylation-dependent regulation of BRAF oncogenic function
Year: 2022
Type: article
Abstract: Aberrant BRAF activation, including the BRAF V600E mutation, is frequently observed in human cancers. However, it remains largely elusive whether other types of post-translational modification(s) in addition to phosphorylation and ubiquitination-dependent regulation also modulate BRAF kinase activity. Here, we report that the acetyltransferase p300 activates the BRAF kinase by promoting BRAF K601 acetylation, a process that is antagonized by the deacetylase SIRT1. Notably, K601 acetylation facilitates BRAF dimerization with RAF proteins and KSR1. Furthermore, K601 acetylation promotes melanoma cell proliferation and contributes to BRAF V600E inhibitor resistance in BRAF V600E harboring melanoma cells. As such, melanoma patient-derived K601E oncogenic mutation mimics K601 acetylation to augment BRAF kinase activity. Our findings, therefore, uncover a layer of BRAF regulation and suggest p300 hyperactivation or SIRT1 deficiency as potential biomarkers to determine ERK activation in melanomas.
Source: Cell Reports
Institutions: Beth Israel Deaconess Medical Center, Harvard University, First Hospital of Jilin University, University of South Florida, Moffitt Cancer Center, Tongji Hospital, Huazhong University of Science and Technology, Sun Yat-sen University, The First Affiliated Hospital, Sun Yat-sen University, First Affiliated Hospital of Xi'an Jiaotong University
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: G3023099107, G4092733956, A Novel Oncogenic Role for Cdc20 Implications in Adult T Cell Leukemia Treatment, Novel regulation of PI3K/Akt to direct targeted breast cancer therapies, G7654313463, A Novel Oncogenic Role for Cdc20 Implications in Adult T Cell Leukemia Treatment, Deciphering the physiological role and interplay between ubiquitination and phosphorylation pathways to guide targeted cancer therapies, Characterizing oncogenic function of ITCH in melanoma
OpenAlex ID: W4205728552